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Review
. 2020 Jul;26(7):1017-1032.
doi: 10.1038/s41591-020-0968-3. Epub 2020 Jul 10.

Extrapulmonary manifestations of COVID-19

Aakriti Gupta #  1   2   3 , Mahesh V Madhavan #  1   2 , Kartik Sehgal #  4   5   6 , Nandini Nair  7 , Shiwani Mahajan  3   8 , Tejasav S Sehrawat  9 , Behnood Bikdeli  1   2   3 , Neha Ahluwalia  10 , John C Ausiello  7 , Elaine Y Wan  1 , Daniel E Freedberg  11 , Ajay J Kirtane  2 , Sahil A Parikh  1   2 , Mathew S Maurer  1 , Anna S Nordvig  12 , Domenico Accili  7 , Joan M Bathon  13 , Sumit Mohan  14   15 , Kenneth A Bauer  4   6 , Martin B Leon  1   2 , Harlan M Krumholz  3   8   16 , Nir Uriel  1 , Mandeep R Mehra  17 , Mitchell S V Elkind  12   15 , Gregg W Stone  2   18 , Allan Schwartz  1 , David D Ho  19 , John P Bilezikian  7 , Donald W Landry  20
Affiliations
Review

Extrapulmonary manifestations of COVID-19

Aakriti Gupta et al. Nat Med. 2020 Jul.

Abstract

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Conflict of interest statement

Competing interests

A. G. received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C. Martin Law Firm for work related to the Cook inferior vena cava filter litigation; received consulting fees from Edward Lifesciences; and holds equity in the healthcare telecardiology startup Heartbeat Health. B. B. reports being a consulting expert, on behalf of the plaintiff, for litigation related to a specific type of inferior vena cava filter. A. J. K. reports institutional funding to Columbia University and/or the Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, Philips, and ReCor Medical. J. M. B. reports an honorarium for participation on a grants review panel for Gilead Biosciences. D. A. is founder, director, and chair of the advisory board of Forkhead Therapeutics. H. M. K. works under contract with the Centers for Medicare & Medicaid Services to support quality measurement programs; was a recipient of a research grant, through Yale University, from Medtronic and the US Food and Drug Administration to develop methods for post-market surveillance of medical devices; was a recipient of a research grant with Medtronic and is the recipient of a research grant from Johnson & Johnson, through Yale University, to support clinical trial data sharing; was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; receives payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation, from the Ben C. Martin Law Firm for work related to the Cook Celect IVC filter litigation, and from the Siegfried and Jensen Law Firm for work related to Vioxx litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; was a participant or participant representative of the IBM Watson Health Life Sciences Board; is a member of the advisory board for Element Science, the advisory board for Facebook, and the physician advisory board for Aetna; and is the co-founder of HugoHealth (a personal health information platform) and co-founder of Refactor Health (an enterprise healthcare AI-augmented data enterprise). M. R. M. reports consulting relationships with Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. D. W. L. is the chair of the scientific advisory board for Applied Therapeutics, licensor of Columbia University technology unrelated to COVID-19 or COVID-19-related therapies.

Figures

Fig. 1 |
Fig. 1 |. Pathophysiology of COVID-19.
SARS-CoV-2 enters host cells through interaction of its spike protein with the entry receptor ACE2 in the presence of TMPRSS2 (far left). Proposed mechanisms for COVID-19 caused by infection with SARS-CoV-2 include (1) direct virus-mediated cell damage; (2) dysregulation of the RAAS as a consequence of downregulation of ACE2 related to viral entry, which leads to decreased cleavage of angiotensin I and angiotensin II; (3) endothelial cell damage and thromboinflammation; and (4) dysregulation of the immune response and hyperinflammation caused by inhibition of interferon signaling by the virus, T cell lymphodepletion, and the production of proinflammatory cytokines, particularly IL-6 and TNFα.
Fig. 2 |
Fig. 2 |. Extrapulmonary manifestations of COVID-19.
The pulmonary manifestation of COVID-19 caused by infection with SARS-CoV-2, including pneumonia and ARDS, are well recognized. In addition, COVID-19 is associated with deleterious effects on many other organ systems. Common extrapulmonary manifestations of COVID-19 are summarized here.
See this image and copyright information in PMC

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